What Clinicians Should Know About Hepatitis C Clinicians Should Know About Hepatitis C Virus Michael…

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  • What Clinicians Should Know

    About Hepatitis C Virus

    Michael S. Saag, MDAssociate Dean, Global Health

    Professor of MedicineDirector, Center for AIDS Research

    University of Alabama at BirminghamBirmingham, Alabama

    FINAL AS OF: 11/15/17

    Slide 3 of 55

    Learning Objectives

    After attending this presentation,

    learners will be able to: Describe the genotypes of HCV and how they relate

    to treatment effects

    Recognize how to stage HCV infection and why it is important to accurately stage

    Recall the clinical presentation of advanced liver disease (cirrhosis)

    Describe emerging treatments of HCV and how the changing landscape will impact treatment decisions in the near future

    Identify new changes to the HCV Guidelines (Sept 2017)

    Slide 5 of 55

    Which test most accurately stage liver fibrosis?

    1. Fibroscan

    2. Fibrosure

    3. APRI

    4. Liver biopsy

    5. Liver percussion

    Fibro

    scan

    Fibro

    sure

    APRI

    Liver

    bio

    psy

    Liver

    per

    cuss

    ion

    27%

    9%

    0%

    64%

    0%

    Louisville, Kentucky, November 17, 2017 1

  • Slide 7 of 55

    What percent of persons with chronic HCV infection develop

    cirrhosis over 30 years?

    1. 0 5%

    2. 6% 20%

    3. 21% 50%

    4. 51% 75%

    5. >75%

    0

    5%

    6%

    2

    0%

    21%

    5

    0%

    51%

    7

    5% >

    75%

    0%

    23% 23%

    15%

    38%

    Slide 9 of 55

    What is the most common genotype of HCV in the United

    States?

    1. Genotype 1

    2. Genotype 2

    3. Genotype 3

    4. Genotype 4

    5. Genotype 56

    Geno

    type

    1

    Geno

    type

    2

    Geno

    type

    3

    Geno

    type

    4

    Geno

    type

    56

    93%

    0% 0%0%7%

    Slide 10 of 55

    Objectives

    Epidemiology

    Natural History

    Staging

    Genome and Drug Targets

    Viral Kinetics With Therapy

    Current Treatments

    What Does SVR Really Mean?

    Louisville, Kentucky, November 17, 2017 2

  • Slide 11 of 55

    Objectives

    Epidemiology

    Natural History

    Staging

    Genome and Drug Targets

    Viral Kinetics With Therapy

    Current Treatments

    What Does SVR Really Mean?

    Slide 12 of 55

    HCV Research Timeline

    Moradpour Nature Reviews 2007; 5:453-463

    AIDS

    1982

    HIV

    1984

    AZT

    1987

    Slide 13 of 55

    HCV Worldwide

    170 million infected

    Highest Asia & Africa

    Egypt > 15%

    USA 1.6% 3-4 million infected

    www.cdc.gov

    Louisville, Kentucky, November 17, 2017 3

  • Slide 14 of 55

    Worldwide prevalence of each HCV genotype by GBD

    HCV genotype 1 (83.4 million cases: 46.2%)- one-third of which are in East Asia.

    Genotype 3 (54.3 million: 30.1%); genotypes 2, 4, and 6 (22.8%); genotype 5

  • Slide 17 of 55

    Objectives

    Epidemiology

    Natural History

    Staging

    Genome and Drug Targets

    Viral Kinetics With Therapy

    Current Treatments

    What Does SVR Really Mean?

    Slide 18 of 55

    Resolved

    Stable

    Slowly

    Progressive

    Transplant/Death

    ~20%

    ~15% ~85%

    ~3%-4%/yr

    ~80%

    ~75%

    ~ 20-year progression rate may beaccelerated with HIV, HBV,

    alcohol, and steatosis1,2Exposure

    (Acute Phase)

    Chronic

    Cirrhosis

    ~4%/yr~6%/yr

    ESLD HCC

    10 20 30Time(yrs)

    5-year survival in patients with HCC is

  • Slide 20 of 55

    Fibrosis/Cirrhosis

    Slide 25 of 55

    Objectives

    Epidemiology

    Natural History

    Staging

    Genome and Drug Targets

    Viral Kinetics With Therapy

    Current Treatments

    What Does SVR Really Mean?

    Slide 26 of 55

    Translation

    HCV NS proteins

    NS2

    Polyprotein

    processing

    NS3

    NS4B

    NS5A NS5B

    HCV RNA

    Fusion and

    uncoating

    RNA

    replication

    NS5A

    CypA

    NS5B

    NS2

    NS3

    NS4B

    Viral

    assembly

    Transport and

    release

    NS3/4A protease inhibitors

    NS5A inhibitors

    NS5B polymerase inhibitors

    NS5A inhibitors

    Potential Therapeutic Targets in the HCV

    Replication Cycle

    Adapted from slide courtesy Ray Chung

    Louisville, Kentucky, November 17, 2017 6

  • Slide 27 of 55

    NUCLEOSIDEINHIBITORS

    Non-NUCLEOSIDEINHIBITORS

    NS5AINHIBITORS

    PROTEASE INHIBITORS

    Slide 28 of 55

    Suffixes Matter!

    - --- PREVIR (Protease / NS3-4a)

    - --- ASVIR (NS5a)

    - --- BUVIR (NS5b)

    Slide 29 of 55

    Agents and Regimens: Fall 2017

    Antiviral

    NS3 NS5ANon-Nuc

    NS5BNuc

    NS5B

    Ledipasvir/sofosbuvir FDC

    Paritaprevir/r/ombitasvir FDC + dasabuvir

    Simeprevir + sofosbuvir

    Glecaprevir / pibrentasvir FDC

    Sofosbuvir + daclatasvir

    Elbasvir/grazoprevir FDC

    Velpatasvir/sofosbuvir FDCVelpat/ Sof / voxilaprevir FDC

    Louisville, Kentucky, November 17, 2017 7

  • Slide 30 of 55

    Objectives

    Epidemiology

    Natural History

    Staging

    Genome and Drug Targets

    Viral Kinetics With Therapy

    Current Treatments

    What Does SVR Really Mean?

    Slide 31 of 55

    On Treatment Viral Kinetics

    2 log decline

    LOD

    Slide 32 of 55

    Objectives

    Epidemiology

    Natural History

    Staging

    Genome and Drug Targets

    Viral Kinetics With Therapy

    Current Treatments

    What Does SVR Really Mean?

    Louisville, Kentucky, November 17, 2017 8

  • Slide 33 of 55

    Chronic HCV prior SOC

    Pegylated IFN + RBV

    48-72 weeks

    Significant AEs

    Response > GT 2/3SV

    R, %

    Fried MW, NEJM 2002

    Manns MP, Lancet 2001

    Slide 34 of 55

    Antiviral HCV treatments

    (FDA-approved as of September, 2017)

    Monotherapies

    IFN-2a

    IFN-2b

    PEG-IFN 2a

    PEG-IFN 2b

    IFN-2a + Ribavirin

    IFN-2b + Ribavirin

    PEG-IFN 2a + Ribavirin*

    PEG-IFN 2b + Ribavirin

    PEG-IFN + ribavirin plus either:

    Boceprevir (GT1)

    Telaprevir (GT1)

    Simeprevir (GT1)

    In combination with other

    agents:

    Sofosbuvir

    Combination Therapies

    Simeprevir + Sofosbuvir (GT1)

    Paritaprevir / ritonavir / ombitasvir

    (FDC) + dasabuvir (GT1)

    Paritaprevir / ritonavir/ ombitasvir

    (FDC) (GT4)

    Daclatasvir + Sofosbuvir

    (GT1,3)*

    Elbasvir + Grazoprevir

    (GT 1, 4)Velpatasvir / Sofosbuvir FDC

    Voxilaprevir / Velpatasvir /

    Sofosbuvir FDC

    Glecaprevir / Pibrentasvir FDC

    Ledipasvir + Sofosbuvir

    (FDC, GT1,4,5,6)

    Pangenotypic Regimens

    (GT 1 6 )

    Slide 35 of 70

    Slide 35 of 55

    Sofosbuvir plus Daclatasvir for GT1

    41n=44 20 2141

    No documented virologic failures. All failures due to missing sample/lost to follow-up or re-infection.

    Louisville, Kentucky, November 17, 2017 9

  • Slide 36 of 70

    Slide 36 of 55

    Slide 36 of 70

    Slide 37 of 55

    Predictors of relapse to sofosbuvir-

    based regimens

    RBVSOF

    RB

    VSO

    F12 weekFISSION

    POSITRON

    FUSION

    VALENCE

    n=285

    24 week

    VALENCE

    n=247

    PE

    G RB

    VSO

    F12 weekATOMIC

    NEUTRINO

    n=339

    Who will do poorly with currently-

    available SOF-based regimens?

    Foster et al. EASL 2014 Abstract 66

    GT177%

    GT29%

    GT310%

    GT44%

    Slide 38 of 55

    Predictors of relapse to sofosbuvir-

    based regimens

    RBVSOF

    RB

    VSO

    F12 weekFISSION

    POSITRON

    FUSION

    VALENCE

    n=285

    24 week

    VALENCE

    n=247

    PE

    G RB

    VSO

    F12 weekATOMIC

    NEUTRINO

    n=339

    Who will do poorly with currently-

    available SOF-based regimens?

    Foster et al. EASL 2014 Abstract 66

    Louisville, Kentucky, November 17, 2017 10

  • Slide 39 of 55

    Predictors of relapse to sofosbuvir-

    based regimens

    RBVSOF

    RB

    VSO

    F12 weekFISSION

    POSITRON

    FUSION

    VALENCE

    n=285

    24 week

    VALENCE

    n=247

    PE

    G RB

    VSO

    F12 weekATOMIC

    NEUTRINO

    n=339

    Who will do poorly with currently-

    available SOF-based regimens?

    Foster et al. EASL 2014 Abstract 66

    Six factors associated with relapse:

    Treatment-experienced

    IL28B non-CC

    Male sex

    Weight > 75 kg

    Cirrhosis

    High viral load >800,000 IU/mL

    Slide 40 of 55

    Updated

    Guidelines

    https://www.hcvguidelines.org

    Slide 42 of 55

    Which of the following statements is true of FDA approval of

    glecaprevir/pibrentasvir?

    1. It is an 8 week regimen only in patients without cirrhosis

    2. It is a 12 week regimen regardless of presence of cirrhosis

    3. It is an 8 week regimen only in treatment nave patients

    4. It is a 16 week regimen in patients with prior treatment experience to DAA

    5. It is a single daily dosed pill

    It is

    an 8

    wee

    k reg

    imen

    onl

    y ..

    It is

    a 12

    wee

    k re

    gim

    en re

    g...

    It is

    an 8

    wee

    k reg

    imen

    onl

    y...

    It is

    a 16

    wee

    k re

    gim

    en in

    p...

    It is

    a sin

    gle d

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